Optimizing therapeutic efficacy in spinal muscular atrophy

Over the last 5 years, three gene targeting therapeutics have been approved for patients with SMA. Despite distinct routes of administration and biodistributions, all show substantially greater efficacy when delivered very early. In order to characterize the mechanisms that may underlie this optimal therapeutic window, we examined SMA and age-matched control human tissues collected during expedited autopsies. We observed high survival motor neuron (SMN) protein expression levels during fetal stages of development that decreased perinatally suggesting a particular requirement for SMN during prenatal development. Parallel histological characterization of motor neuron axons in human and SMA mouse ventral roots indicated that impairments of motor axon radial growth and Schwann ensheathment began in utero and were followed by rapid degeneration postnatally. In SMA mice, in utero treatment with small molecule SMN2 splice modifiers was required to more fully restore motor axonal maturation programs and prevent axon degeneration. Together these studies provide a cellular basis for the fulminant worsening of infantile onset SMA patients and emphasize that minimizing neonatal treatment delay is essential to achieve optimal outcomes. These studies also provide a rationale for exploring fetal treatment of patients with the most severe forms of SMA.